NY State community health center sites were surveyed in 2012 to assess the availability of alcohol, tobacco, and other drug services for the underserved. Surveys were completed from 156 of 251 adult ...primary care clinical sites (62% response rate). Seventy-one percent of sites had guidelines requiring screening for mental health problems while less than half (46%) had guidelines for substance use disorders. In practice, 55% of clinics reported nearly all adults were screened for mental health disorders compared to 32% of adults for substance use disorders (SUD). Forty three percent of sites that screened patients for SUD did not use a standard screening instrument. More than three quarters of sites offered tobacco cessation services while 17% reported offering SUD treatment. Findings from multi-level analyses suggested that FQHC organizations influence sites' SUD screening requirements but not the provision of on-site treatment. Analyses further suggested that neither geographic setting (urban/rural) nor the size of the FQHC organization influenced screening requirements or on-site treatment availability. Although more research is needed to explore differences between site and organizational level reporting, this study suggests that SUD screening rates remain low among FQHC primary care sites, but that FQHC organization could improve rates across sites by requiring SUD screening using a standard instrument.
Abstract
Introduction:
Tumor mutational burden (TMB) is the number of somatic mutations per megabase in a tumor's genome and has shown promise as a predictive biomarker of response to immune ...checkpoint inhibitors across several cancers. TMB is typically measured by whole exome sequencing (WES TMB) or by targeted next-generation sequencing gene panels (panel TMB). As more assays are developed to estimate TMB, harmonization is emerging as an unmet need and is a key goal of the Friends of Cancer Research (Friends) TMB Harmonization Project. Phase I of the Harmonization Project demonstrated correlation between panel TMB and WES TMB using TCGA data and defined theoretical sources of variability across panels. In phase IIA, sustainable TMB reference standard materials generated from human derived cell lines were used to characterize variability in TMB measurements across panels and assessed for utility in TMB alignment. Phase IIB aims to characterize variability in TMB measurements in clinical samples and to establish best practices for estimating and aligning TMB in order to improve consistency across panels.
Methods:
Fifteen laboratories (16 targeted gene panels) at different stages of development participated in phase IIB. Thirty formalin-fixed paraffin-embedded (FFPE) samples with >30% tumor content were acquired; tumor DNA was isolated by a single reference lab. TMB values were calculated for DNA extracted from lung (N=10), bladder (N=10), and gastric tumors (N=10) using WES and a uniform bioinformatics pipeline agreed upon by all Consortium members. DNA samples were also sent to all laboratories, and each used their own sequencing and bioinformatics pipelines to estimate TMB from the genes represented in their respective panels. For each tumor sample, a median across panel TMB estimates was calculated; individual panel TMB estimates were translated to fold-changes relative to the sample median to quantify variability. Association between WES TMB (reference) and panel TMB will be assessed by regression analysis; dependence of association on cancer type was investigated.
Results:
A subset of tumor samples (9 bladder, 7 lung, and 5 gastric) was analyzed using 11 panels at the time of abstract submission. Median panel TMB values ranged 0.60 - 40.26 across samples, with median of median values of 5.35. Fold-change from sample-level medians ranged 0x - 6.67x. Assessment of these clinical samples by WES and all 16 gene panels, as well as regression analysis results, are forthcoming.
Conclusions:
The Friends TMB Harmonization Project has made substantial progress in characterization of TMB measurement variability and association between WES TMB and panel TMB. These are important steps toward alignment of TMB estimates generated by different gene panels which may improve the interpretation of findings within clinical development programs and ultimately enhance the usefulness of this predictive biomarker in clinical decision making.
Citation Format: Diana M. MERINO, Laura M. Yee, Lisa M. McShane, P. Mickey Williams, Tomas Vilimas, Rajesh Patidar, J. Carl Barrett, Shu-Jen Chen, Jen-Hao Cheng, Jeffrey M. Conroy, Dinesh Cyanam, Kenneth R. Eyring, David A. Fabrizio, Vincent Funari, Elizabeth P. Garcia, Sean T. Glenn, Christopher D. Gocke, Vikas Gupta, Lisa M. Haley, Matthew D. Hellmann, Laurel Keefer, Lauryn R. Keeler, Brett Kennedy, Alexander J. Lazar, Laura E. MacConaill, Kristen L. Meier, Arnaud Papin, Naiyer A. Rizvi, Ethan Sokol, Phillip Stafford, John F. Thompson, Warren Tom, Victor J. Weigman, Mingchao Xie, Chen Zhao, Mark D. Stewart, Jeff Allen. Alignment of TMB measured on clinical samples: Phase IIB of the Friends of Cancer Research TMB Harmonization Project abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5671.
Novel trisubstituted ethylenes, halogen ring-substituted propyl 2-cyano-3-phenyl-2-propenoates, RPhCH ˭ C(CN)CO
2
C
3
H
7
(where R is 2-Br, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F, 4-F were prepared ...and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and propyl cyanoacetate, and characterized by CHN analysis, IR,
1
H and
13
C-NMR. All the ethylenes were copolymerized with styrene (M
1
) in solution with radical initiation (ABCN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR,
1
H and
13
C-NMR. Decomposition of the copolymers in nitrogen occurred in two steps, first in the 200-500°C range with residue (0.9-4.7% wt.), which then decomposed in the 500-800°C range.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Instead of reacting via the expected coarctate cyclization pathway, 2-nitrosobenzonitrile undergoes a tandem nitroso-ene/intramolecular cyclization to form benzocisoxazol-3(1H)-imines in very good ...yields under neutral conditions and at moderate temperatures. Treatment of three of the imines with HBF4 results in dimerization/condensation to furnish unusual, delocalized cationic systems.
Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, ...or gene–environment interactions is not well understood.
We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case–control study of African-American females and males (1078 lung cancer cases and 822 controls).
Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09×10−5). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527A(betaSNP*CPD=−0.017, p=0.0061, corrected p=0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.
These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.
•Genetic by environment (e.g., cigarettes/day, CPD) interactions for lung cancer are understudied in non-European ancestry populations.•We analyzed interactions between nominal smoking quantity SNPs (n=7156 discovery sample) and CPD and risk of lung cancer (n=1078 cases, n=822 controls).•Six SNPs were effect modifiers of CPD for lung cancer, suggesting that the allelic dose effect is most pronounced in light smokers.
Lung cancer is the leading cause of cancer death, disproportionately affecting African-Americans. Prior studies have reported specific genetic markers linked to both smoking quantity and risk of lung cancer in multiple ethnic/racial groups. Investigators analyzed associations between 28 polymorphisms and average cigarettes smoked per day (CPD) in 7156 African-American females and examined interactions between the top polymorphisms and CPD in a cohort of African-American males and females (1078 lung cancer cases and 822 health control patients). The results suggested that six polymorphisms within one genomic region increased lung cancer risk in African-Americans, which was most pronounced in light smokers.
A Mercury orbiter mission is challenging from thermal and mass perspectives. The Mercury Surface, Space Environment, Geochemistry, and Ranging (MESSENGER) mission overcomes these challenges while ...avoiding esoteric technologies by using an innovative approach with commonly available materials, minimal moving parts, and maximum heritage. This approach yields a spacecraft with good margins in all categories and low technical risk. The key concepts are a ceramic-cloth sunshade, an integrated lightweight structure and high- performance propulsion system, and a solar array incorporating optical solar reflectors (OSRs). The sunshade maintains the spacecraft at room temperature. The integrated structure and propulsion system provides ample mass margin. The solar array with OSRs, which has already undergone significant testing, provides thermal margin even if the panels are inadvertently pointed directly at the Sun at 0.3 AU.
0.3
AU
.
Scrub typhus threatens one billion people in the Asia-Pacific area and cases have emerged outside this region. It is caused by infection with any of the multitude of strains of the bacterium ...'Orientia tsutsugamushi'. A vaccine that affords heterologous protection and a commercially-available molecular diagnostic assay are lacking. Herein, we determined that the nucleotide and translated amino acid sequences of outer membrane protein A (OmpA) are highly conserved among 51 'O. tsutsugamushi' isolates. Molecular modeling revealed the predicted tertiary structure of 'O. tsutsugamushi' OmpA to be very similar to that of the phylogenetically-related pathogen, 'Anaplasma phagocytophilum', including the location of a helix that contains residues functionally essential for A. phagocytophilum infection. PCR primers were developed that amplified ompA DNA from all 'O. tsutsugamushi' strains, but not from negative control bacteria. Using these primers in quantitative PCR enabled sensitive detection and quantitation of 'O. tsutsugamushi' ompA DNA from organs and blood of mice that had been experimentally infected with the Karp or Gilliam strains. The high degree of OmpA conservation among 'O. tsutsugamushi' strains evidences its potential to serve as a molecular diagnostic target and justifies its consideration as a candidate for developing a broadly-protective scrub typhus vaccine.
The Pseudomonas aeruginosa fimbrial structures encoded by the cup gene clusters (cupB and cupC) contribute to its attachment to abiotic surfaces and biofilm formation. The P. aeruginosa pvcABCD gene ...cluster encodes enzymes that synthesize a novel isonitrile functionalized cumarin, paerucumarin. Paerucumarin has already been characterized chemically, but this is the first report elucidating its role in bacterial biology. We examined the relationship between the pvc operon and the cup gene clusters in the P. aeruginosa strain MPAO1. Mutations within the pvc genes compromised biofilm development and significantly reduced the expression of cupB1-6 and cupC1-3, as well as different genes of the cupB/cupC two-component regulatory systems, roc1/roc2. Adjacent to pvc is the transcriptional regulator ptxR. A ptxR mutation in MPAO1 significantly reduced the expression of the pvc genes, the cupB/cupC genes, and the roc1/roc2 genes. Overexpression of the intact chromosomally-encoded pvc operon by a ptxR plasmid significantly enhanced cupB2, cupC2, rocS1, and rocS2 expression and biofilm development. Exogenously added paerucumarin significantly increased the expression of cupB2, cupC2, rocS1 and rocS2 in the pvcA mutant. Our results suggest that pvc influences P. aeruginosa biofilm development through the cup gene clusters in a pathway that involves paerucumarin, PtxR, and different cup regulators.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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